A global phase 3 study evaluated the pharmacokinetics, efficacy, and safety of recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) in 63 previously treated male patients ...(12-61 years) with severe hemophilia B (factor IX FIX activity ≤2%). The study included 2 groups: group 1 patients received routine prophylaxis once every 7 days for 26 weeks, followed by either 7-, 10-, or 14-day prophylaxis regimen for a mean of 50, 38, or 51 weeks, respectively; group 2 patients received on-demand treatment of bleeding episodes for 26 weeks and then switched to a 7-day prophylaxis regimen for a mean of 45 weeks. The mean terminal half-life of rIX-FP was 102 hours, 4.3-fold longer than previous FIX treatment. Patients maintained a mean trough of 20 and 12 IU/dL FIX activity on prophylaxis with rIX-FP 40 IU/kg weekly and 75 IU/kg every 2 weeks, respectively. There was 100% reduction in median annualized spontaneous bleeding rate (AsBR) and 100% resolution of target joints when subjects switched from on-demand to prophylaxis treatment with rIX-FP (P < .0001). The median AsBR was 0.00 for all prophylaxis regimens. Overall, 98.6% of bleeding episodes were treated successfully, including 93.6% that were treated with a single injection. No patient developed an inhibitor, and no safety concerns were identified. These results indicate rIX-FP is safe and effective for preventing and treating bleeding episodes in patients with hemophilia B at dosing regimens of 40 IU/kg weekly and 75 IU/kg every 2 weeks. This trial was registered at www.clinicaltrials.gov as #NCT0101496274.
•rIX-FP maintains mean trough of 20 and 12 IU/dL FIX activity with 40 IU/kg weekly and 75 IU/kg every 2 weeks prophylaxis, respectively.•Weekly and 14-day prophylaxis regimens with rIX-FP were well tolerated and provided low bleeding rates and target joint improvement.
Numerous reports of vascular events after an initial recovery from COVID-19 form our impetus to investigate the impact of COVID-19 on vascular health of recovered patients. We found elevated levels ...of circulating endothelial cells (CECs), a biomarker of vascular injury, in COVID-19 convalescents compared to healthy controls. In particular, those with pre-existing conditions (e.g., hypertension, diabetes) had more pronounced endothelial activation hallmarks than non-COVID-19 patients with matched cardiovascular risk. Several proinflammatory and activated T lymphocyte-associated cytokines sustained from acute infection to recovery phase, which correlated positively with CEC measures, implicating cytokine-driven endothelial dysfunction. Notably, we found higher frequency of effector T cells in our COVID-19 convalescents compared to healthy controls. The activation markers detected on CECs mapped to counter receptors found primarily on cytotoxic CD8
T cells, raising the possibility of cytotoxic effector cells targeting activated endothelial cells. Clinical trials in preventive therapy for post-COVID-19 vascular complications may be needed.
SARS-CoV-2 is the novel coronavirus responsible for the current COVID-19 pandemic. Severe complications are observed only in a small proportion of infected patients but the cellular mechanisms ...underlying this progression are still unknown. Comprehensive flow cytometry of whole blood samples from 54 COVID-19 patients reveals a dramatic increase in the number of immature neutrophils. This increase strongly correlates with disease severity and is associated with elevated IL-6 and IP-10 levels, two key players in the cytokine storm. The most pronounced decrease in cell counts is observed for CD8 T-cells and VD2 γδ T-cells, which both exhibit increased differentiation and activation. ROC analysis reveals that the count ratio of immature neutrophils to VD2 (or CD8) T-cells predicts pneumonia onset (0.9071) as well as hypoxia onset (0.8908) with high sensitivity and specificity. It would thus be a useful prognostic marker for preventive patient management and improved healthcare resource management.
Background
Phase 3 randomized clinical trials have been designed to compare secondary cytoreductive surgery followed by systemic therapy with systemic therapy alone for management of patients with ...recurrent ovarian cancer. This study aimed to compare differences in clinical outcomes between these two treatment approaches.
Methods
The PRISMA statement was applied. Only phase 3 randomized clinical trials were included in the final analysis.
Results
Three randomized clinical trials (
n
= 1250 patients) were identified. Secondary cytoreductive surgery was associated with significantly better progression-free survival (PFS) improvement than systemic therapy alone (hazard ratio HR, 95% CI, 0.61–0.78;
p
< 0.001). The PFS benefit was greater for the complete resection subpopulation (HR, 0.56; 95% CI, 0.48–0.66;
p
< 0.001). The HR of overall survival (OS) was similar between the groups (HR, 0.93; 95% CI, 0.78–1.10;
p
= 0.37), but it was 0.73 (95% CI, 0.59–0.91) in favor of the complete resection subpopulation.
Conclusion
This meta-analysis showed secondary cytoreductive surgery as superior to systemic therapy alone in terms of PFS. The PFS and OS benefits were particularly observed for complete surgical resection. The impact on OS in the general population remains to be proven.
Global hydrology has come a long way since the first introduction of the primitive land surface model of Manabe (1969) and the declaration of the “Emergence of Global Hydrology” by Eagleson (1986). ...Hydrological submodels of varying complexity are now part of global climate models, of models calculating global terrestrial carbon sequestration, of earth system models, and even of integrated assessment models. This paper reviews the current state of global hydrological modeling, discusses past and recent developments, and extrapolates these to future challenges and directions. First, established domains of global hydrological model applications are discussed, in terms of societal and science questions posed, the type of models developed, and recent advances therein. Next, a genealogy of global hydrological models is given. After reviewing recent efforts to connect model components from different domains, new domains are identified where global hydrology is now starting to become an integral part of the analyses. Finally, inspired by these new domains of application, persistent and emerging challenges are identified as well as the directions global hydrology is likely to take in the coming decade and beyond.
Key Points:
Review of global hydrology over the period 1969–2015
Identification of recent trends
Vision on future trends and challenges
Deceased donor kidneys are preserved in cold hypoxic conditions. Providing oxygen during preservation might improve post-transplant outcomes, particularly for kidneys subjected to greater degrees of ...preservation injury. This study aimed to investigate whether supplemental oxygen during hypothermic machine perfusion (HMP) could improve the outcome of kidneys donated after circulatory death.
This randomised, double-blind, paired, phase 3 trial was done in 19 European transplant centres. Kidney pairs from donors aged 50 years or older, donated after circulatory death, were eligible if both kidneys were transplanted into two different recipients. One kidney from each donor was randomly assigned using permuted blocks to oxygenated hypothermic machine perfusion (HMPO2), the other to HMP without oxygenation. Perfusion was maintained from organ retrieval to implantation. The primary outcome was 12-month estimated glomerular filtration rate (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration equation in pairs of donated kidneys in which both transplanted kidneys were functioning at the end of follow-up. Safety outcomes were reported for all transplanted kidneys. Intention-to-treat analyses were done. This trial is registered with the ISRCTN Registry, ISRCTN32967929, and is now closed.
Between March 15, 2015, and April 11, 2017, 197 kidney pairs were randomised with 106 pairs transplanted into eligible recipients. 23 kidney pairs were excluded from the primary analysis because of kidney failure or patient death. Mean eGFR at 12 months was 50·5 mL/min per 1·73 m2 (SD 19·3) in the HMPO2 group versus 46·7 mL/min per 1·73m2 (17·1) in HMP (mean difference 3·7 mL/min per 1·73m2, 95% CI −1·0 to 8·4; p=0·12). Fewer severe complications (Clavien-Dindo grade IIIb or more) were reported in the HMPO2 group (46 of 417, 11%, 95% CI 8% to 14%) than in the HMP group (76 of 474, 16%, 13% to 20%; p=0·032). Graft failure was lower with HMPO2 (three 3% of 106) compared with HMP (11 10% of 106; hazard ratio 0·27, 95% CI 0·07 to 0·95; p=0·028).
HMPO2 of kidneys donated after circulatory death is safe and reduces post-transplant complications (grade IIIb or more). The 12-month difference in eGFR between the HMPO2 and HMP groups was not significant when both kidneys from the same donor were still functioning 1-year post-transplant, but potential beneficial effects of HMPO2 were suggested by analysis of secondary outcomes.
European Commission 7th Framework Programme.
The cytochrome P450 (P450) enzymes are the major catalysts involved in the metabolism of drugs. Bioavailability and toxicity are 2 of the most common barriers in drug development today, and P450 and ...the conjugation enzymes can influence these effects. The toxicity of drugs can be considered in 5 contexts: on-target toxicity, hypersensitivity and immunological reactions, off-target pharmacology, bioactivation to reactive intermediates, and idiosyncratic drug reactions. The chemistry of bioactivation is reasonably well understood, but the mechanisms underlying biological responses are not. In the article we consider what fraction of drug toxicity actually involves metabolism, and we examine how species and human interindividual variations affect pharmacokinetics and toxicity.
A numerical model was developed to analyse the mechanical behaviour of fresh, 3D printed concrete, in the range of 0 to 90 min after material deposition. The model was based on a time-dependent ...Mohr-Coulomb failure criterion and linear stress-strain behaviour up to failure. An experimental program, consisting of unconfined uniaxial compression tests and direct shear tests, was set-up and performed to obtain the required material properties. The material tests showed that the Young's modulus and cohesion linearly increase with fresh concrete age, as do the compressive and shear strength. The Poisson's ratio and angle of internal friction, on the other hand, remain constant. Subsequently, the model was validated by comparison to printing experiments. Modelling of the printed samples reproduced the experimental results qualitatively, but the quantitative agreement with the print experiments could be improved. However, the deviations can well be explained and the type of failure-deformation mode was predicted accurately.
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